Luo Yuchuan, Yan Chang, Wang Jing, Wang Chenjun, Yu Hongji, Yin Xintong, Wu Yingjie, Liu Ning, Qin Yinghe
State Key Laboratory of Animal Nutrition and Feeding, China Agricultural University, 2 Yuanmingyuan West Road, Haidian, Beijing, 100193, P.R. China.
Reprod Sci. 2025 Aug 13. doi: 10.1007/s43032-025-01955-y.
Orchitis, a prevalent male reproductive disorder that can severely impair fertility and potentially result in infertility. Sertoli cells orchestrate testicular immune responses during orchitis by modulating local inflammation and maintaining blood-testis barrier integrity. While Myeloid differentiation primary response protein 88 (MyD88), a critical adaptor molecule in the TLR4 signaling pathway, is known to mediate immune responses, its cell-specific role in Sertoli cells during lipopolysaccharide (LPS)-induced orchitis remains elusive. Using an murine orchitis model established through intraperitoneal LPS administration, we observed pronounced testicular inflammation concurrent with dramatic upregulation of MyD88 protein levels (P < 0.05). To further investigate the Sertoli cell-specific function of MyD88, we generated conditional Myd88 knockout (cKO) mice. Compared to controls, cKO mice showed marked attenuation of testicular edema along with improved sperm motility and viability post-LPS challenge. Myd88 deletion also suppressed LPS-triggered surges in pro-inflammatory cytokines (TNF-α, IL-6), maintained seminiferous tubule architecture, and mitigated neutrophil infiltration. Further studies demonstrated that Myd88 deletion rescued LPS-induced BTB disruption by restoring the expression of key BTB components (Connexin43, Claudin-11). Additionally, NF-κB signaling pathway is activated by MyD88 mediated inflammatory responses. Collectively, these findings uncover Sertoli cell specific MyD88 as a key regulator in LPS-induced orchitis pathogenesis, highlighting its potential as a promising therapeutic target for orchitis.
睾丸炎是一种常见的男性生殖系统疾病，可严重损害生育能力并可能导致不育。在睾丸炎期间，支持细胞通过调节局部炎症和维持血睾屏障完整性来协调睾丸的免疫反应。虽然髓样分化初级反应蛋白88（MyD88）是Toll样受体4（TLR4）信号通路中的关键衔接分子，已知其介导免疫反应，但其在脂多糖（LPS）诱导的睾丸炎中在支持细胞中的细胞特异性作用仍不清楚。通过腹腔注射LPS建立小鼠睾丸炎模型，我们观察到明显的睾丸炎症，同时MyD88蛋白水平显著上调（P < 0.05）。为了进一步研究MyD88在支持细胞中的特异性功能，我们构建了条件性Myd88基因敲除（cKO）小鼠。与对照组相比，cKO小鼠在LPS攻击后睾丸水肿明显减轻，精子活力和存活率提高。Myd88缺失还抑制了LPS触发的促炎细胞因子（TNF-α、IL-6）激增，维持了生精小管结构，并减轻了中性粒细胞浸润。进一步研究表明，Myd88缺失通过恢复关键血睾屏障成分（连接蛋白43、闭合蛋白11）的表达挽救了LPS诱导的血睾屏障破坏。此外，MyD88介导的炎症反应激活了核因子κB（NF-κB）信号通路。总之，这些发现揭示了支持细胞特异性的MyD88是LPS诱导的睾丸炎发病机制中的关键调节因子，突出了其作为睾丸炎有前景的治疗靶点的潜力。
